Effects of in utero androgen excess and metformin treatment on hepatic functions

This study aimed to evaluate the role of prenatal hyperandrogenization in liver functions and the extent of metformin as treatment. Pregnant rats were hyperandrogenized with subcutaneous testosterone (1mg/rat) between 16 and 19 of pregnancy. Prenatally hyperandrogenized (PH) female offspring displayed, at the adult life, two phenotypes; a PH irregular ovulatory phenotype (PHiov) and a PH anovulatory (PHanov) phenotype. From day 70 to the moment of sacrifice (90 days of age), 50% of the animals of each group received a daily oral dose of 50 mg/kg of metformin. We found that both PH phenotypes displayed a hepatic disruptions of insulin and glucose pathway and that metformin treatment reversed some of these alterations in a specific-phenotype manner. Our findings show, for the first time, that androgen excess in utero promotes hepatic dysfunctions and that metformin treatment is able to specifically reverse those hepatic alterations and sheds light on the possible mechanisms of metformin action.Fil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Heber, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferrer, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferreira, Silvana Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Silva, Aimé Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Background:It is still unelucidated how hormonal alterations affect developing organisms and their descendants. Particularly, the effects of androgen levels are of clinical relevance as they are usually high in women with Polycystic Ovary Syndrome (PCOS). Moreover, it is still unknown how androgens may affect males’ health and their descendants.Objectives:We aimed to evaluate the multigenerational effect of prenatal androgen excess until a second generation at early developmental stages considering both maternal and paternal effects.Design And Methods:This is an animal model study. Female rats (F0) were exposed to androgens during pregnancy by injections of 1 mg of testosterone to obtain prenatally hyperandrogenized (PH) animals (F1), leading to a well—known animal model that resembles PCOS features. A control (C) group was obtained by vehicle injections. The PH-F1 animals were crossed with C males (m) or females (f) and C animals were also mated, thus obtaining 3 different mating groups: Cf × Cm, PHf × Cm, Cf × PHm and their offspring (F2).Results:F1-PHf presented altered glucose metabolism and lipid profile compared to F1-C females. In addition, F1-PHf showed an increased time to mating with control males compared to the C group. At gestational day 14, we found alterations in glucose and total cholesterol serum levels and in the placental size of the pregnant F1-PHf and Cf mated to F1-PHm. The F2 offspring resulting from F1-PH mothers or fathers showed alterations in their growth, size, and glucose metabolism up to early post-natal development in a sex-dependent manner, being the females born to F1-PHf the most affected ones.Conclusion:androgen exposure during intrauterine life leads to programing effects in females and males that affect offspring health in a sex-dependent manner, at least up-to a second generation. In addition, this study suggests paternally mediated effects on the F2 offspring development.Fil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferreira, Silvana Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferrer, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Silva, Aimé Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Hyperandrogenism and Polycystic ovary syndrome: Effects in pregnancy and offspring development

Polycystic ovary syndrome (PCOS) is one of the major endocrine disorders affecting women of reproductive age. Its etiology remains unclear. It is suggested that environmental factors, and particularly the intrauterine environment, play key roles in PCOS development. Besides the role of androgens in PCOS pathogenesis, exposure to endocrine disruptors, as is Bisphenol A, could also contribute to its development. Although PCOS is considered one of the leading causes of ovarian infertility, many PCOS patients can get pregnant. Some of them by natural conception and others by assisted reproductive technique treatments. As hyperandrogenism (one of PCOS main features) affects ovarian and uterine functions, PCOS women, despite reaching pregnancy, could present high-risk pregnancies, including implantation failure, an increased risk of gestational diabetes, preeclampsia, and preterm birth. Moreover, hyperandrogenism may also be maintained in these women during pregnancy. Therefore, as an altered uterine milieu, including hormonal imbalance, could affect the developing organisms, monitoring these patients throughout pregnancy and their offspring development is highly relevant. The present review focuses on the impact of androgenism and PCOS on fertility issues and pregnancy-related outcomes and offspring development. The evidence suggests that the increased risk of pregnancy complications and adverse offspring outcomes of PCOS women would be due to the factors involved in the syndrome pathogenesis and the related co-morbidities. A better understanding of the involved mechanisms is still needed and could contribute to a better management of these women and their offspring. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors.Fil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Silva, Aimé Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Velazquez, Mariela Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferrer, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Background: It is still unelucidated how hormonal alterations affect developing organisms and their descendants. Particularly, the effects of androgen levels are of clinical relevance as they are usually high in women with Polycystic Ovary Syndrome (PCOS). Moreover, it is still unknown how androgens may affect males’ health and their descendants. Objectives: We aimed to evaluate the multigenerational effect of prenatal androgen excess until a second generation at early developmental stages considering both maternal and paternal effects. Design And Methods: This is an animal model study. Female rats (F0) were exposed to androgens during pregnancy by injections of 1 mg of testosterone to obtain prenatally hyperandrogenized (PH) animals (F1), leading to a well—known animal model that resembles PCOS features. A control (C) group was obtained by vehicle injections. The PH-F1 animals were crossed with C males (m) or females (f) and C animals were also mated, thus obtaining 3 different mating groups: Cf × Cm, PHf × Cm, Cf × PHm and their offspring (F2). Results: F1-PHf presented altered glucose metabolism and lipid profile compared to F1-C females. In addition, F1-PHf showed an increased time to mating with control males compared to the C group. At gestational day 14, we found alterations in glucose and total cholesterol serum levels and in the placental size of the pregnant F1-PHf and Cf mated to F1-PHm. The F2 offspring resulting from F1-PH mothers or fathers showed alterations in their growth, size, and glucose metabolism up to early post-natal development in a sex-dependent manner, being the females born to F1-PHf the most affected ones. Conclusion: androgen exposure during intrauterine life leads to programing effects in females and males that affect offspring health in a sex-dependent manner, at least up-to a second generation. In addition, this study suggests paternally mediated effects on the F2 offspring development

Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats

It is known that prenatal hyperandrogenization induces alterations since early stages of life, contributing to the development of polycystic ovary syndrome affecting the reproductive axis and the metabolic status, thus promoting others associated disorders, such as dyslipidemia, insulin resistance, liver dysfunction, and even steatosis. In this study, we aimed to evaluate the effect of fetal programming by androgen excess on the hepatic lipid content and metabolic mediators at adult life. Pregnant rats were hyperandrogenized with daily subcutaneous injections of 1 mg of free testosterone from days 16 to 19 of pregnancy. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory phenotype (PHiov) and anovulatory phenotype (PHanov), with different metabolic and endocrine features. We evaluated the liver lipid content and the main aspect of the balance between fatty acid (FA) synthesis and oxidation. We investigated the status of the peroxisomal proliferator-activated receptors (PPARs) alpha and gamma, which act as lipid mediators, and the adipokine chemerin, one marker of liver alterations. We found that prenatal hyperandrogenization altered the liver lipid profile with increased FAs levels in the PHanov phenotype and decreased cholesterol content in the PHiov phenotype. FA metabolism was also disturbed, including decreased mRNA and protein PPARgamma levels and impaired gene expression of the main enzymes involved in lipid metabolism. Moreover, we found low chemerin protein levels in both PH phenotypes. In conclusion, these data suggest that prenatal hyperandrogenization exerts a negative effect on the liver and alters lipid content and metabolic mediators' expression at adult age.Fil: Silva, Aimé Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferrer, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Heber, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferreira, Silvana Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Cerrone, Gloria Edith. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector boson pairs in proton-proton collisions at root s=13 TeV

A search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector bosons, using proton-proton collisions at root s = 13 TeV at the LHC, is reported. The data sample corresponds to an integrated luminosity of 137 fb(-1) collected with the CMS detector. Events are selected by requiring two or three electrons or muons, moderate missing transverse momentum, and two jets with a large rapidity separation and a large dijet mass. No excess of events with respect to the standard model background predictions is observed. Model independent upper limits at 95% confidence level are reported on the product of the cross section and branching fraction for vector boson fusion production of charged Higgs bosons as a function of mass, from 200 to 3000 GeV. The results are interpreted in the context of the Georgi-Machacek model.Peer reviewe

Strange hadron collectivity in pPb and PbPb collisions

International audienceThe collective behavior of ${\textrm{K}}_{\textrm{S}}^0$ and $\Lambda /\overline{\Lambda}$ strange hadrons is studied by measuring the elliptic azimuthal anisotropy (v$_{2}$) using the scalar-product and multiparticle correlation methods. Proton-lead (pPb) collisions at a nucleon-nucleon center-of-mass energy $\sqrt{s_{\textrm{NN}}}$ = 8.16 TeV and lead-lead (PbPb) collisions at $\sqrt{s_{\textrm{NN}}}$ = 5.02 TeV collected by the CMS experiment at the LHC are investigated. Nonflow effects in the pPb collisions are studied by using a subevent cumulant analysis and by excluding events where a jet with transverse momentum greater than 20 GeV is present. The strange hadron v$_{2}$ values extracted in pPb collisions via the four- and six-particle correlation method are found to be nearly identical, suggesting the collective behavior. Comparisons of the pPb and PbPb results for both strange hadrons and charged particles illustrate how event-by-event flow fluctuations depend on the system size.[graphic not available: see fulltext

Search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector boson pairs in proton–proton collisions at s=13 TeV\sqrt{s} = 13\,{\text {TeV}}

A search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector bosons, using proton–proton collisions at $\sqrt{s}=13\,{\text {TeV}}$ at the LHC, is reported. The data sample corresponds to an integrated luminosity of 137$\,{\text {fb}}^{-1}$ collected with the CMS detector. Events are selected by requiring two or three electrons or muons, moderate missing transverse momentum, and two jets with a large rapidity separation and a large dijet mass. No excess of events with respect to the standard model background predictions is observed. Model independent upper limits at 95% confidence level are reported on the product of the cross section and branching fraction for vector boson fusion production of charged Higgs bosons as a function of mass, from 200 to 3000$\,{\text {GeV}}$. The results are interpreted in the context of the Georgi–Machacek model

Search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector boson pairs in proton–proton collisions at s=13 TeV\sqrt{s} = 13\,{\text {TeV}}

A search for charged Higgs bosons produced in vector boson fusion processes and decaying into vector bosons, using proton–proton collisions at $\sqrt{s}=13\,{\text {TeV}}$ at the LHC, is reported. The data sample corresponds to an integrated luminosity of 137$\,{\text {fb}}^{-1}$ collected with the CMS detector. Events are selected by requiring two or three electrons or muons, moderate missing transverse momentum, and two jets with a large rapidity separation and a large dijet mass. No excess of events with respect to the standard model background predictions is observed. Model independent upper limits at 95% confidence level are reported on the product of the cross section and branching fraction for vector boson fusion production of charged Higgs bosons as a function of mass, from 200 to 3000$\,{\text {GeV}}$. The results are interpreted in the context of the Georgi–Machacek model